1. Field of the Invention
This invention relates to biological applications of alkaloids derived from the tunicate Eudistoma sp. and related compounds, and to the preparation of synthetic pyridoacridines.
2. Background of the Related Art.
In recent years it has become apparent that the sea offers an enormous biomedical potential. The marine environment is quite distinct from the terrestrial environment and a vast number of marine natural products with novel molecular architectures were already isolated and purified from diverse marine organisms. Surprisingly, only a small fraction of these novel compounds underwent detailed pharmacological and biological evaluations and only few of these were found to possess desirable biological and physiological activities, see Scheuer, "Marine Natural Products, Chemical and Biological Perspectives", Academic Press, New York, Vols. I-V, (1978-1983); Kaul et al., Ann. Rev. Pharmacol., 26, 117-142 (1986); Scheuer, Science, 248, 173-177 (1990).
The inventors have been engaged in the last 10 years in a research endeavor that involves chemical, biochemical and cell biological studies of marine natural products derived from Red Sea organisms. This interconnected effort has already yielded what others have described as "perhaps the most stimulating compounds isolated from corals and sponges"- the latrunculins. See Kaul et al., Ann. Rev. Pharmacol., 26. 117-142 (1986). The latrunculins, isolated from the Red Sea sponge, latrunculia maonifica react specifically with the actin-based cytoskeleton and appear to be the most powerful probes currently available for the pharmacological investigation of microfilament organization and function, See: Spector et al., Science. 214, 493-495 (1983); Coue et al., FEBS Lett., 213, 316-318 (1987) and Spector et al., "Cell Motility and the Cytoskeleton", 13, 127-144 (1989). Also see, U.S. Pat. No. 4,857,538 to Kashman et al. entitled New Compounds for the Study and Treatment of Microfiliment Organization in cells.
Recently, two of the co-inventors, Drs. Kashman and Rudi have isolated and purified six (6) new heterocyclic alkaloids from the purple tunicate Eudistoma sp. and have elucidated their structures, See Rudi et al., Tetrahedron Lett., 29, 665-668 (1988); Rudi et al., Tetrahedron Lett., 29, 3861-3862 (1988) and Rudi et al., J. Org. Chem., 54, 5331-5337 (1989). The structures of these six (6) heterocyclic alkaloids (1) segoline A; (2) segoline B; (3) isosegoline A; (4) norsegoline; (5) Debromoshermilamine; and (6) Eilatin are shown in FIG. 1. The six (6) Eudistoma alkaloids have in common a fused tetracyclic benzo-3,6-diazaphenanthroline ring system that was first identified in the sponge metabolite amphimedine, see Schmitz et al., J. Am. Chem. Soc., 105, 4835-4837 (1983) and more recently in some other polycyclic aromatic alkaloids isolated from unrelated marine organisms including sponges, tunicates (ascidians), and an anemone see for example, Cimino et al., Tetrahedron, 43, 4023-4024 (1987 ); Bloor et al., J. Am. Chem. Soc., 109, 6134-6136 (1987); Cooray et al., J. Org. Chem., 53, 4619-4620 (1988); Molinsky et al., J. Org. Chem., 53, 1340-1341 (1988); Kobayashi et al., J. Org. Chem., 53, 1800-1804 (1988); Kobayashi et al., Tetrahedron Lett., 29, 1177-1180 (1988); Charyulu et al., Tetrahedron Lett., 30, 4201-4202 (1989); Molinski et al., J. Org. Chem., 54, 4256-4259 (1989); and Schmitz et al., J. Org. Chem., 56, 804-808 (1991).
Based on chemical structure, the Eudistoma alkaloids have been classified into 4 groups:
1. Three of the compounds display a high degree of structural similarity and were designated as Segoline A, segoline B, and Isosegoline A (segol means purple in Hebrew).
2. A fourth compound, lacks the imide moiety that is present in the above three compounds and was designated Norsegoline.
3. Another compound contains a thiazinone moiety. It was designated Debromoshermilamine A because it was found to be closely related to Shermilamine, a compound previously purified from a different tunicate trididemnum sp. found in Pago Bay, Guam, as reported by Cooray et al., J. Org. Chem., 53, 4619-4620 (1988).
4. The last compound was designated Eilatin (from tunicate collected in Eilat) is the most remarkable in having a rare, highly symmetrical heptacyclic structure.
In addition to these six (6) natural compounds, Drs. Kashman and Rudi have synthesized several derivatives of Segoline A as shown in Scheme I at FIG. 2(A), Segoline B as shown in Scheme II at FIG. 2(B); see, Rudi et al., J. Org. Chem., 59, 5331-5337 (1989).
Chemically, the six (6) Eudistoma alkaloids appear to belong to a growing class of novel marine alkaloids that have in common a fused tetracyclic benzo-3,6-diazaphenanthroline ring system. There are scant reports concerning the biological activities of these related species indicating that many of them are cytotoxic to a variety of cancer cell lines see Cimino et al., Tetrahedron, 43, 4023 (1987); Bloor et al., J. Am. Chem. Soc., 109, 6134 (1987); Molinski et al., J. Org. Chem., 53, 1340 (1988); Kobayashi et al., J. Org. Chem., 53, 1800 (1988); Kobayashi et al., Tetrahedron Lett., 29, 1177 (1988); Charyulu et al., Tetrahedron Lett., 30, 4201 (1989); Molinski et al., J. Org. Chem., 54, 4256 (1989); Schmitz et al., J. Org. Chem., 56, 804 (1991) but the mechanism by which they exert their cytotoxic effects is completely unknown.
At present it is not even clear whether all these novel marine alkaloids should be classed together, and whether they are produced by the source organism or by symbionts, see Rudi et al., J. Org. Chem., 54, 5331-5337 (1989). The presence of six different alkaloids in the same Eudistoma sp. organism is without precedent and provides a unique opportunity to shed some light on these problems.